Many studies have shown that green tea possesses anti-inflammatory properties. We recently showed that DBA/1 mice given green tea polyphenols (GTP) in drinking water had clinically mild arthritis and little histological evidence of cartilage damage and bone erosion. Several factors, including pro-inflammatory cytokines, contribute to the destruction of an arthritic joint. Osteoarthritis (OA) is the most common degenerative joint disorder in which the pro-inflammatory cytokine IL-1 has been shown to play a decisive role. Its effects include the inhibition of attempted cartilage repair and enhanced degradation of cartilage matrix, induction of collagenases and the second messenger nitric oxide (NO). Data from our preliminary studies showed that when the green tea catechin epigallocatechin-3-gallate (EGCG) was added to human chondrocyte cultures (1) inhibited IL-1 -induced cartilage matrix degradation; (2) inhibited IL-1 -induced production of NO; (3) inhibited IL-1 -induced activation of nuclear factor kappa B (NF-kB); and (4) mitogen activated protein kinase (MAPK) sub-groups c-jun amino terminal kinase (JNK) and p38-MAPK. Work proposed in this application is based on this solid preliminary data and is designed to understand in depth how EGCG inhibits IL-1-induced cartilage degradation. Using human chondrocytes we will investigate (1) the inhibition of IL-1-induced nitric oxide synthase (iNOS) gene expression by EGCG; (2) the modulation of stress responsive transcription factor NF-kB by EGCG; (3) modulation of activator protein-1 (AP-1) and the transcription factor RUNX-2 by EGCG; (4) inhibition of the MAPK signal transduction pathways by EGCG; and (5) inhibition of MMP-1 3 gene expression by EGCG. Results of these studies are expected to define the molecular basis of the anti-inflammatory effects of EGCG on human chondrocytes. The long term objective of these studies is to explore the use of EGCG or compounds derived from it in inhibiting the onset and or progression of cartilage destruction in arthritis.